Chronicle down memory lane: India's sixty years of plague experience

BackgroundThis perspective documents the historical aspects of outbreaks of plague of last six decades, establishment of plague surveillance network in India with detailed insights about its activities and recent developments requiring focus on plague surveillance. Human plague was reported in Mulbagal area of Karnataka in 1966-67 only to re-emerge in the country in 1994 in Beed district (Maharashtra) and subsequently in Surat (Gujarat). Later Plague outbreak has been reported in the year 2002 with index case from Village Hatkoti, Shimla District in Himachal Pradesh. The last outbreak reported from India was in 2004 from Village Dangaud, Uttarkashi District in Uttarakhand followed by a period of quiescent since last 17 years.ObjectivesDuring the last few decades, at least three geographical areas experienced outbreaks of plague after silent period of 28 years. We recapitulate the response mechanism for containing outbreaks during the last three outbreaks of plague held in Maharashtra & Gujarat (1994), Himachal Pradesh (2002) and Uttarakhand (2004). We also document the Plague surveillance network of India and its activities which is a comprehensive surveillance system comprising of rodent, flea, canine and human surveillance whose foundation was started in 1964. The recent developments of last decade in terms of revised Human plague surveillance case definitions, Plague surveillance sites, vector control, novel diagnostics and vaccines in our country are also mentioned.ConclusionThe thrust areas in control of plague outbreak are early detection and isolation of cases, timely effective antibiotic treatment, chemoprophylaxis to contacts, strengthening of surveillance system and massive IEC campaign in infected areas. Yersinia pestis (causative agent of Plague) also being an important bioterrorism agent, clinicians need to pay special attention to diagnose and microbiologists must be provided skilled training for laboratory confirmation to this pestilential disease for effective and timely management.     

Rapid Detection and Simultaneous Antibiotic Susceptibility Analysis of Yersinia pestis Directly from Clinical Specimens by Use of Reporter Phage

Yersinia pestis is a tier 1 agent due to its contagious pneumopathogenicity, extremely rapid progression, and high mortality rate. As the disease is usually fatal without appropriate therapy, rapid detection from clinical matrices is critical to patient outcomes. We previously engineered the diagnostic phage ΦA1122 with luxAB to create a “light-tagged” reporter phage. ΦA1122::luxAB rapidly detects Y. pestis in pure culture and human serum by transducing a bioluminescent signal response. In this report, we assessed the analytical specificity of the reporter phage and investigated diagnostic utility (detection and antibiotic susceptibility analysis) directly from spiked whole blood. The bioreporter displayed 100% (n = 59) inclusivity for Y. pestis and consistent intraspecific signal transduction levels. False positives were not obtained from species typically associated with bacteremia or those relevant to plague diagnosis. However, some non-pestis Yersinia strains and Enterobacteriaceae did elicit signals, albeit at highly attenuated transduction levels. Diagnostic performance was assayed in simple broth-enriched blood samples and standard aerobic culture bottles. In blood, <10² CFU/ml was detected within 5 h. In addition, Y. pestis was identified directly from positive blood cultures within 20 to 45 min without further processing. Importantly, coincubation of blood samples with antibiotics facilitated simultaneous antimicrobial susceptibility profiling. Consequently, the reporter phage demonstrated rapid detection and antibiotic susceptibility profiling directly from clinical samples, features that may improve patient prognosis during plague outbreaks.     

Ritual Circumcision in the Age of Germ Theory Amongst Nineteenth-Century New York Immigrants

While Jewish ritual circumcision continues to be a controversial issue in Europe and the US, metzitzah b’peh, the addendum to brit milah, which requires the mohel (ritual peritomist) to orally suck blood from the wound immediately following the excision of the foreskin, remains a divisive topic. While medical historians have studied European outbreaks of infectious disease following metzitzah b’peh, no one has assessed the response of the nineteenth century New York Jewry. This paper analyses how this nascent community responded to the thorough report by the New York Board of Health following an alleged and discredited outbreak of syphilis attributed to metzitzah b’peh in 1873, especially in the context of nineteenth century immigration, popular perception of syphilis and American medicine. Keywords : Ritual Circumcision, Metzitzah b’peh, Syphilis, Syphilophobia, Mohel, Lower East Side     

新疆伊犁维吾尔族,哈萨克族和蒙古族指纹白线正常值分析

对我国新疆伊犁维吾尔族，哈萨克族和蒙古族共１３７５人的指纹白线正常值分布进行了研究。这三个民族的指纹白线出现率分别是２３．３６％，２０．３１％和９．２％，并进行了性别，指别和不同民族间差异的比较。     

Reflections on crisis burials related to past plague epidemics

Drawing its etymology from the Latin pestis (curse), plague, over the centuries, has been more dreaded by humankind than any other epidemic. The Apocalypse had recognized plague as the archetypal divine curse, ‘the power to kill over a fourth of the earth'. Plague is thus a particular topic of study, insofar that it is one of the rare epidemics that has had recurrent major consequences on demography and human societies. Its highly transmissible nature, the brutality of its action, its high pathogenicity, marked by strong lethality and great swiftness, and the complete absence of treatment options before the 20th century conferred on it a sinister aspect. Generating a series of severe demographic crises, well known in the Western world, it has necessarily influenced the evolution of societies at both the biological and cultural levels.     

Whole-genome sequencing of Campylobacter jejuni isolated from Danish routine human stool samples reveals surprising degree of clustering

ObjectivesOutbreaks of Campylobacter are traditionally considered to be rare; however, rather than being the true nature of the disease, this may reflect our present inability to detect them. The aim of this study was to determine the genetic and epidemiological degree of clustering among Campylobacter jejuni isolates from Danish patients.MethodsWhole-genome sequencing (WGS) was applied to 245 C. jejuni isolates from patients with domestically acquired infection over a 9-month period in 2015 and 2016.ResultsWGS demonstrated that 62 of the 245 isolates (25%) clustered genetically. In total, 21 genetic clusters were identified of which four (18%) consisted of five isolates or more. Seventeen (81%) of the 21 genetic clusters were clustered in space and/or time. Of the 245 isolates, 49 (20%) were part of a temporal and/or geographical cluster. The identified clusters included two outbreaks; one which had not been identified through the existing surveillance system.ConclusionsUsing WGS, we show that Campylobacter case clustering and even outbreaks appear to occur more often than previously assumed, providing important new insight into the relatively poorly understood epidemiology of the most important cause of bacterial gastroenteritis in the industrialized world.     

Observations on the 1348 plague epidemic. Measures taken to combat its tragic effects and avoid epidemic recrudescence

When the "Black Death" swept through Europe from southern France in 1348, in the short space of two years the Europeans were hit by one of the most serious epidemics ever recorded in human history. Yersinia pestis reached Europe by sea, its contamination propagated by the Genoese ships coming from the Crimean port of Jaffa. For the first time the world experienced microbiological unification: East and West were equally involved in the tragedy that spread, and no town remained unscathed during the various epidemic waves which succeeded one another in the following three centuries. The authors of this article describe how and why the epidemic spread, as well as the factors that led to the swift, and often fatal, involment of millions of Europeans. The second part of the article deals with the measures taken by the healthcare authorities of European towns and countries in order to halt the proliferation of the disease. According to the data and observations by authoritative authors, selected among the many who studied the disease that from the 14th century spread like a scourge throughout the known world at the time, the epidemic could have been even more serious, in terms of mortality and morbidity, without the disciplinary and provisional health measures taken. The experience gained in Italy and all over Europe at the time proved useful not only to better manage the epidemics which cyclically broke out, but also to efficiently combat the cholera epidemics of the 19th century. With the 14th century plague epidemic, the Europeans and their political and administrative representatives may well have realized for the very first time that contamination could be combatted by adopting a set of rational, scientific norms - although in practice such rules were mostly inspired by misguided scientific theories. Humankind was no longer alone. A new society was emerging, one that was not going to passively accept the more or less mysterious ways of a superior being of fate. The Italian and German city-states, the emerging nations (France, England, Austria, Spain, Holland) developed and adopted procedures to control the epidemic - at the first on an ad hoc basis, then permanently. Sometimes success was achieved but always at a high price on the part of the individual and the local community. The path to an epidemic-free existence for humankind was still a long one.     

Deletion of Braun Lipoprotein and Plasminogen-Activating Protease-Encoding Genes Attenuates Yersinia pestis in Mouse Models of Bubonic and Pneumonic Plague

Currently, there is no FDA-approved vaccine against Yersinia pestis, the causative agent of bubonic and pneumonic plague. Since both humoral immunity and cell-mediated immunity are essential in providing the host with protection against plague, we developed a live-attenuated vaccine strain by deleting the Braun lipoprotein (lpp) and plasminogen-activating protease (pla) genes from Y. pestis CO92. The Δlpp Δpla double isogenic mutant was highly attenuated in evoking both bubonic and pneumonic plague in a mouse model. Further, animals immunized with the mutant by either the intranasal or the subcutaneous route were significantly protected from developing subsequent pneumonic plague. In mice, the mutant poorly disseminated to peripheral organs and the production of proinflammatory cytokines concurrently decreased. Histopathologically, reduced damage to the lungs and livers of mice infected with the Δlpp Δpla double mutant compared to the level of damage in wild-type (WT) CO92-challenged animals was observed. The Δlpp Δpla mutant-immunized mice elicited a humoral immune response to the WT bacterium, as well as to CO92-specific antigens. Moreover, T cells from mutant-immunized animals exhibited significantly higher proliferative responses, when stimulated ex vivo with heat-killed WT CO92 antigens, than mice immunized with the same sublethal dose of WT CO92. Likewise, T cells from the mutant-immunized mice produced more gamma interferon (IFN-γ) and interleukin-4. These animals had an increasing number of tumor necrosis factor alpha (TNF-α)-producing CD4⁺ and CD8⁺ T cells than WT CO92-infected mice. These data emphasize the role of TNF-α and IFN-γ in protecting mice against pneumonic plague. Overall, our studies provide evidence that deletion of the lpp and pla genes acts synergistically in protecting animals against pneumonic plague, and we have demonstrated an immunological basis for this protection.     

Evaluation of rodent bait containing imidacloprid for the control of fleas on commensal rodents in a plague-endemic region of northwest Uganda

In recent decades, the majority of human plague cases (caused by Yersinia pestis) have been reported from Africa. In an effort to reduce the risk of the disease in this area, we evaluated the efficacy of a host-targeted rodent bait containing the insecticide imidacloprid for controlling fleas on house-dwelling commensal rodents in a plague-endemic region of northwestern Uganda. Results demonstrated that the use of a palatable, rodent-targeted, wax-based bait cube was effective at reducing the prevalence of fleas on commensal rodents and flea burdens on these animals at day 7 postbait exposure, but lacked significant residual activity, allowing flea populations to rebound in the absence of additional bait applications. Our results indicate the use of a palatable host-targeted bait block containing imidacloprid was an effective technique for quickly reducing flea numbers on rodents in northwest Uganda and, thus, could be useful for lowering the potential risk of human flea bite exposures during plague outbreaks if applied continuously during the period of risk.     

Infectious Disease Outbreaks in Competitive Sports, 2005–2010

Context

Old, evolving, and new infectious agents continually threaten the participation of competitors in sports.

Objective

To provide an update of the medical literature on infectious disease outbreaks in sport for the last 5 years (May 2005–November 2010).

Main Outcome Measure(s)

A total of 21 outbreaks or clusters were identified.

Results

Methicillin-resistant Staphylococcus aureus (n = 7, 33%; mainly community acquired) and tinea (trichophytosis: n = 6, 29%) were the most common pathogens responsible for outbreaks. Skin and soft tissue was the most common site of infection (n = 15, 71%).

Conclusions

The majority of outbreaks reported occurred in close-contact sports, mainly combat sports (ie, wrestling, judo) and American football. Twelve outbreaks (57%) involved high school or collegiate competitors. Common community outbreak pathogens, such as influenza virus and norovirus, have received little attention.Key Words: methicillin-resistant Staphylococcus aureus, tinea, trichophytosis, pathogens, athletes

Key Points

• Most reported outbreaks occurred in competitors participating in close contact sports.
• Of the reported outbreaks, 71% involved infections of the skin and soft tissue.
• Methicillin-resistant Staphylococcus aureus accounted for 33% of reported outbreaks.
• High school or collegiate competitors were affected in 57% of reported outbreaks.

It has been more than 5 years since Turbeville et al¹ performed a literature review identifying 59 infectious disease outbreaks or clusters among athletes in competitive sports from 1922 through May 2005. They found that herpes simplex virus (HSV) and Staphylococcus aureus were the most common pathogens reported. However, new or evolving pathogens continue to emerge, posing potentially significant risks to the health of competitors.In 2009, the world experienced its first global influenza virus pandemic since 1968; infections occurred more commonly in younger people.^2,3 Within the last decade, community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has continued to emerge, with outbreaks and increasing rates reported in several countries.⁴ Infectious diseases commonly disrupt both an individual athlete''s participation in sports and a team''s ability to perform.It is clearly important that the nature of outbreaks of infection among athletes are documented and delineated so that preventive measures may be undertaken. In an ever-changing environment, a review that spanned more than 80 years may not provide an accurate reflection of the pathogens currently of concern among sports competitors.¹ With this 5-year update of infectious disease outbreaks in sports, our goal was to provide a current picture of the pathogens involved in published outbreaks in athletes.     

Evaluation of Protective Potential of Yersinia pestis Outer Membrane Protein Antigens as Possible Candidates for a New-Generation Recombinant Plague Vaccine

Plague caused by Yersinia pestis manifests itself in bubonic, septicemic, and pneumonic forms. Although the U.S. Food and Drug Administration recently approved levofloxacin, there is no approved human vaccine against plague. The capsular antigen F1 and the low-calcium-response V antigen (LcrV) of Y. pestis represent excellent vaccine candidates; however, the inability of the immune responses to F1 and LcrV to provide protection against Y. pestis F1⁻ strains or those which harbor variants of LcrV is a significant concern. Here, we show that the passive transfer of hyperimmune sera from rats infected with the plague bacterium and rescued by levofloxacin protected naive animals against pneumonic plague. Furthermore, 10 to 12 protein bands from wild-type (WT) Y. pestis CO92 reacted with the aforementioned hyperimmune sera upon Western blot analysis. Based on mass spectrometric analysis, four of these proteins were identified as attachment invasion locus (Ail/OmpX), plasminogen-activating protease (Pla), outer membrane protein A (OmpA), and F1. The genes encoding these proteins were cloned, and the recombinant proteins purified from Escherichia coli for immunization purposes before challenging mice and rats with either the F1⁻ mutant or WT CO92 in bubonic and pneumonic plague models. Although antibodies to Ail and OmpA protected mice against bubonic plague when challenged with the F1⁻ CO92 strain, Pla antibodies were protective against pneumonic plague. In the rat model, antibodies to Ail provided protection only against pneumonic plague after WT CO92 challenge. Together, the addition of Y. pestis outer membrane proteins to a new-generation recombinant vaccine could provide protection against a wide variety of Y. pestis strains.     

Identification of a Human Monoclonal Antibody To Replace Equine Diphtheria Antitoxin for Treatment of Diphtheria Intoxication

Diphtheria antitoxin (DAT) has been the cornerstone of the treatment of Corynebacterium diphtheriae infection for more than 100 years. Although the global incidence of diphtheria has declined steadily over the last quarter of the 20th century, the disease remains endemic in many parts of the world, and significant outbreaks still occur. DAT is an equine polyclonal antibody that is not commercially available in the United States and is in short supply globally. A safer, more readily available alternative to DAT would be desirable. In the current study, we obtained human monoclonal antibodies (hMAbs) directly from antibody-secreting cells in the circulation of immunized human volunteers. We isolated a panel of diverse hMAbs that recognized diphtheria toxoid, as well as a variety of recombinant protein fragments of diphtheria toxin. Forty-five unique hMAbs were tested for neutralization of diphtheria toxin in in vitro cytotoxicity assays with a 50% effective concentration of 0.65 ng/ml for the lead candidate hMAb, 315C4. In addition, 25 μg of 315C4 completely protected guinea pigs from intoxication in an in vivo lethality model, yielding an estimated relative potency of 64 IU/mg. In comparison, 1.6 IU of DAT was necessary for full protection from morbidity and mortality in this model. We further established that our lead candidate hMAb binds to the receptor-binding domain of diphtheria toxin and physically blocks the toxin from binding to the putative receptor, heparin-binding epidermal growth factor-like growth factor. The discovery of a specific and potent human neutralizing antibody against diphtheria toxin holds promise as a potential therapeutic.     

The 'Hittite plague', an epidemic of tularemia and the first record of biological warfare

A long-lasting epidemic that plagued the Eastern Mediterranean in the 14th century BC was traced back to a focus in Canaan along the Arwad-Euphrates trading route. The symptoms, mode of infection, and geographical area, identified the agent as Francisella tularensis, which is also credited for outbreaks in Canaan around 1715 BC and 1075 BC. At first, the 14th century epidemic contaminated an area stretching from Cyprus to Iraq, and from Israel to Syria, sparing Egypt and Anatolia due to quarantine and political boundaries, respectively. Subsequently, wars spread the disease to central Anatolia, from where it was deliberately brought to Western Anatolia, in what constitutes the first known record of biological warfare. Finally, Aegean soldiers fighting in western Anatolia returned home to their islands, further spreading the epidemic.     

Efficient tracing of global isolates of Yersinia pestis by restriction fragment length polymorphism analysis using three insertion sequences as probes

Yersinia pestis is the etiologic agent of plague, a disease that is transmitted from rodent to rodent and from rodent to humans by fleabites. Multiple copies of three insertion sequences (IS100, IS285, and IS1541) are scattered over the Y. pestis genome. The genomic instability generated by these insertion sequences (IS) creates a polymorphism of the hybridizing restriction fragments (restriction fragment length polymorphism [RFLP]) which can be used to subtype this relatively clonal species. The aim of this work was to evaluate and compare the potential of the three IS-RFLP techniques, individually or in combination, to define clusters of strains according to their focus of origin. The analysis of 61 Y. pestis isolates of worldwide origin indicated that no satisfactory strain clustering was observed with each IS-RFLP used individually. In contrast, the combination of the three IS-RFLP data (3IS-RFLP) resulted in both an efficient strain discrimination (D = 0.999) and a robust clustering of the isolates according to their biovar and geographical origin. This geographical clustering was observed even within the Orientalis group, although these strains had only a short period of time (one century) to diverge from the original clone that spread globally. Therefore, 3IS-RFLP is a technique that may be useful for addressing epidemiological problems and forensic issues. When plague reemerges after several decades of silence in a quiescent focus, it may help in determining whether the disease was reimported or reactivated. It may also be of value to identify the origin of a strain when plague cases appear in a previously plague-free region. Finally, this technique could be useful for the tracing of a Y. pestis isolate that has been used as a biological terrorism threat.     

Vaccines for emerging pathogens: from research to the clinic

In this two-part series of reviews, we have invited experts in their fields to contribute articles on the status of vaccine research and development for emerging pathogens. This topic has been brought into sharp focus in recent years following significant outbreaks of viral diseases such as those causing severe acute respiratory syndrome and Middle East respiratory syndrome, as well as devastating outbreaks of diseases caused by the Ebola, Marburg, Zika and Lassa fever viruses, to name only a few examples. Additionally, bacterial infections leading to bubonic and pneumonic plague, most notably in Madagascar in 2018, as well as malaria in many tropical countries, melioidosis in south east Asia and tularaemia in northern Europe and North America, have incurred significant morbidity and mortality. In this review series, the life cycle of these pathogens and the epidemiology of disease have been reviewed in the context of potential points of intervention for the prevention of human infection. Many of the emerging pathogens are zoonoses and, as such, there is scope for intervention at the animal/insect/environmental reservoir. Other pathogens covered in this review series are considered to be re-emerging, such as multi-drug resistant tuberculosis.     

Changes in serotypes and antimicrobial susceptibility of invasive Streptococcus pneumoniae strains in Cleveland: a quarter century of experience

The serotypes and susceptibilities to penicillin, macrolides, and clindamycin of 1,655 invasive isolates of Streptococcus pneumoniae recovered between 1979 and 2004 were determined. A precipitous decrease of 61% in the number of isolates was found following 2000, the year of 7-valent protein-conjugated pneumococcal vaccine (PCV7) introduction (139 versus 55 per 2-year period prior to versus after 2000; P < 0.001). This decrease was 84% in children <5 years old (80 versus 13 per 2-year period; P < 0.001) and 18 to 23% in other age groups (P, not significant). PCV7 serotypes decreased by 76% overall (103 versus 25 per 2-year period; P < 0.001) and by 92% in children <5 years old (65 versus 5 per 2-year period; P < 0.001), with significant decreases in six of the seven PCV serotypes. Other serotypes, except for type 19A, decreased from 32 to 22 per 2-year period, while type 19A increased from 4 to 8 per 2-year period, although none of these changes reached significance. Drug resistance emerged slowly, with the first penicillin-intermediate strain isolated in 1980 and the first macrolide/lincosamide-resistant strain isolated in 1984. The first penicillin-resistant strain was isolated in 1993. Resistance increased steadily thereafter until 2003-2004, when 51.1% of isolates were penicillin nonsusceptible and 53.3% were macrolide resistant. Clindamycin resistance remained low until 2003-2004, when 26.7% of strains were resistant; this was associated with the emergence of multidrug-resistant type 19A strains. This study documents the emergence of resistance over a quarter century among invasive pneumococci in the Cleveland area, as well as the reduction in disease caused by PCV7 serotypes following the introduction of PCV7 in 2000.     

Modelling the black death. A historical case study and implications for the epidemiology of bubonic plague

We analysed a plague outbreak in the mining town of Freiberg in Saxony which started in May 1613 and ended in February 1614. This epidemic was selected for study because of the high quality of contemporary sources. It was possible to identify 1400 individual victims meaning that more than 10% of the population of the city perished. The outbreak was modelled by 9 differential equations describing flea, rat, and human populations. This resulted in a close fit to the historical records of this outbreak. An interesting implication of the model is that the introduction of even a small number of immune rats into an otherwise unchanged setting results in an abortive outbreak with very few human victims. Hence, the percentage of immune rats directly influences the magnitude of a human epidemic by diverting search activities of the fleas. Thus, we conclude that the spread of Rattus norvegicus, which might acquire partial herd immunity by exposure to soil- or water-borne Yersinia species due to its preference for wet habitats, contributed to the disappearance of Black Death epidemics from Europe in the 18th century. In order to prove whether or not the parameter values obtained by fitting a given outbreak are also applicable to other cases, we modelled the plague outbreak in Bombay 1905/06 using the same parameter values except for the number of humans as well as of immune and susceptible rats.     

The Eyam plague revisited: did the village isolation change transmission from fleas to pulmonary?

Back in the 17th century the Derbyshire village of Eyam fell victim to the Black Death, which is thought to have arrived from London in some old clothes brought by a travelling tailor. The village population was 350 at the commencement of plague, of which only 83 survived. Led by the church leaders, the village community realized that the whole surrounding region was at risk from the epidemic, and therefore decided to seal themselves off from the other surrounding villages. In the first 275 days of the outbreak, transmission was predominantly from infected fleas to susceptible humans. From then onward, mortality sharply increased, which indicates a changing in transmission pattern. We hypothesize that the confinement facilitated the spread of the infection by increasing the contact rate through direct transmission among humans. This would be more consistent with pulmonary plague, a deadlier form of the disease. In order to test the above hypothesis we designed a mathematical model for plague dynamics, incorporating both the indirect (fleas-rats-humans) and direct (human-to-human) transmissions of the infection. Our results show remarkable agreement between data and the model, lending support to our hypotheses. The Eyam plague episode is celebrated as a remarkable act of collective self-sacrifice. However, to the best of our knowledge, there were no evidence before that the confinement actually increased the burden payed by the commoners. In the light of our results, it can be said that the hypothesis that confinement facilitated the spread of the infection by increasing the contact rate through direct transmission is plausible.